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HYPOGLYCEMIA UPDATE By-Dawit Ayele Nov,2006 OUTLINE -Hypoglycemic disorders-in diabetics -non diabetics -Complications -Diagnosis -Management I-Hypoglycemic disorders in Diabetes Study –2/3 of patients admitted for hypo are diabetics -2/3 used alcohol Clinical context - Hyperglycemia treatment were it not for hypo. would be easy. - Hypoglycemia makes diabetes mgt complex. Due to this :-chronic complications-retinopathy,neuropathy etc..progress despite aggressive attempts. -plasma glucose may be <50mg/dl in ~10% of the time. -average 2 episodes of sxic hypoglycemia per week & severe temporarily disabling hypoglycemia 1-2Xa year. -2-4%of death of such people Risk Factors I-Excess insulin: 1-Ill timed,wrong type & high dose 2- glucose influx 3- insulin independent glucose utilization. 4-endogenous glucose production(alcohol,renal parenchyma dis.) 5- insulin sensitivity.(post exercise) 6- insulin clearance.(renal failure) II-Interplay of insulin excess & compromised glucose counterregulation A-Absolute insulin deficiency(-ve C-Peptide) ß-cell destruction:no in insulin in response to glucose hence:No in glucagon in response to glucose B-History of severe hypglycemia or aggressive therapy per se.(lower glucose goals,lower Hgb A1c) Episodes of attenuated autonomic hypoglycemia including epinephrine activation & sxs in response to glucose defective glucose counter regulation& hypoglycemia unawareness II-Non-Diabetic Hypoglycemic Disorders A-The Fasting(Post absorptive)hypoglycemias i-Drugs Insulin,sulfonylureas -Most common causes(in rx of diabetes) -sometimes taken surreptitiously -taken for criminal intent -pharmacy/other error Mechanisms--described Drugs con’t Ethanol -Inhibits gluconeogenesis(deplets cofactor key to entry of gluconeogenesis precursors.) -inhibits cortisol &GH responses. -Doesn’t inhibit glycogenolysis. Clinical alcohol induced hypo. Typically follows 6-36 hours post binge of moderate to heavy alcohol while the patient eats little. Prolonged hypoglycemia in diabetics who took alcohol is potentially fatal. Drugs con’t Salicylates —in large doses(4-6gm/d) & sulfonamides Can cause hypoglycemia in children. Mechanism is unknown but it may involve increased insulin secretion from the pancreas. · Quinine plasma insulin:glucagon ratio Drugs con’t Pentamidine: is ß-cell toxin,especially in prolonged duration of Rx, dose,renal insufficiency. *Initially can cause hypo. By causing insulin release;later cause diabetes. Study-Rx for PCP-7%experienced hypoglycemia -14%hypoglycemia followed by diabetes. -18%diabetes without hypoglycemia Drugs con’t Non selective ßblockers:(eg.Propranolol) cause hypoglycemia especially in insulin treated diabetes patients by: - symptoms of developing hypoglycemia - impair epinephrine mediated glucose counterregulation. so better use selective ßblockers Atenolol/Metoprolol in diabetics on Rx. ii-Critical Illnesses Common in hospitalized patients 2nd to drugs. -Extensive liver disease -esp.rapid & massive destruction.egfulminant viral hepatitis,fatty liver due to alcohol,cholangitis&biliary obstruction &10malignant tumors( IGFIIproduction) -Unusual in common forms of cirrhosis & hepatitis&metastatic liver disease. Illness con’t Severe Cardiac Failure -Unknown pathogenesis -Possibly due to hepatic congestion, hypoxia&gluconeogenetic precursor limitation. -inhibited gluconeogenesis(studies showed increased blood lactate) Illness con’t Renal failure -Unknown pathogenesis -Compromised glucose counter regulation is probable -Studies suggest : glucose turnover gluconeogenesis(fasting glucose level & no increase in lactate) usually cachectic loss of precursor for gluconeogenesis in diabetic nephropathy with exogenous insulin Rx insulin clearance Illness con’t Sepsis -relatively common cause -glucose utilization by macrophage rich tissue stimulated by cytokines(TNF,IL6) -hypoglycemia develops when hepatic glucose production decreases due to: - hepatic responsiveness to appropriate glucoregulatory stimuli. -hepatic hypo perfusion(esp.in septic shock) Hormonal Deficiencies glucagon& epinephrine + insulinhypoglycemia “ “ -insulin+hypoglycemia Cortisol,GH or both(hypopituitarism) no hypo in most adults; -can occasionally cause during high glucose utilization(exercise/pregnancy/alcohol) Children esp.neonates would have hypoglycemia preceded by caloric deprivation Epinephrine secretion due to cortisol defn.might contribute to mild hypoglycemia. such patients have no glucagon - Non ß-cell tumors Small percentage of patients developed severe hypo. Usually large tumors of mesenchymal & epithelial cell types ~2-4kgs located 1/3in chest&2/3retroperitoneum. -no single pathogenetic mechanism explains all cases -Major cause appears to be glucose utilization due to tumoral secretion of IGFII(index study 25 out of 28 pts had IGFII) - Other factors --glu.utilization by tumor & sk.ms,metastatic hepatic tissue replacement, gluconeogenesis… Endogenous Hyperinsulinism Pancreatic ß-cell d/o-- Insulinoma Rare 0.4/100,000 Early1920-insulin discovered for diabetes Rx -clinical events of insulin identified as new disease hyperinsulinism. 1927-malignant pancreatic islet-cell tumor found in a patient with severe hypoglycemia tumor extracts caused marked hypo.in rats. 1929-1st cure of insulinism by tumor removal. -Mechanism of insulin maintenance –unknown Study-variant of insulin mRNA with translation efficiency -**Hypoglycemia-due to hepatic glucose output rather than glucose utilization. B-Post prandial(reactive hypoglycemia) Occurs only after meals & self limited Occurs in children with certain rare enzymatic defects.(fructose intolerance..) In some individuals who have undergone gastric surgeryrapid passage of food from stomach to intestinerapid in plasma glucoseinduce extuberent insulinhypoglycemia Complications 1-recurrent/persistent psychosocial morbidity(Emotional lability,irritability,depression). 2-Fear of hypoglycemia-barrier for diabetic control. 3-Seizure 4-permanent neurologic deficit (including cognitive impairment) 5-Coma 6-Death Approach to the patient Steps: 1-Recognition & documentation 2-Diagnosis of hypoglycemia 3-Urgent treatment 4-Prevention of recurrent hypoglycemia Recognition & documentation Draw blood before glucose administration Convincing documentation-Whipple’s triad Obscure cause-check additional assays -glucose -insulin -C-peptide -sulfonyluria levels -Cortisol -Ethanol Note-Normal blood glucose with free symptoms doesn’t exclude hypoglycemia -Distinctly low plasma glucose without history of corresponding symptoms is probably laboratory error. eg.abnormally high leukocyte,erythrocyte,platelet count;delayed separation of serum from elements Diagnosis of Hypoglycemia Hypoglycemia: -non specific manifestations -vary among individuals -change from time to time -Episodic Diagnosis :can not be made solely on sn&sx &on basis of plasma glucose Whipple’s triad is the clinical key for diagnosis. Diagnosis con’t **72-Hours supervised test -oldest best established & probably most reliable test for evaluation of hypoglycemia. -Its though complicated & expensive-reserved for those w/o reasonable diagnosis. Approach to testing: Purpose-provoke homeostatic response Reasons-confirm hypoglycemia is cause of pts’sx. -check if reversing it relieves sxs(whiple’s triad) Diagnosis con’t Protocol of Mayo clinic: -Date onset of fast;continue non essential medics. -Allow calorie free & caffeine free beverages -Ensure patient is active during waking hrs. -Collect blood specimens for pl.glu,insulin,C-peptide & pro-insulin Q6hrly till Pl.Glu.<60then Q 1-2hrly Test end points:-Pl. glu.<45mg/dl -pt has sx or sn of hypoglycemia -72 hrs have elapsed -Steps after fast end:-measure plasma ß-hydroxybutyrate& sulfonylurea concn. -1mg of glucagon given IV& plasma glu.measured 10,20,30minutes later -Patient is fed. By observing the biochemical values along with sn & sx its usually possible to distinguish various causes!! Diagnosis con’t Interpretation: - ß-hydroxybutyrate value+vigorous plasma glucose response to IV glucagonHypoglycemia mediated by insulin or insulin like factor - Plasma insulin,C-peptide,& pro insulin valueInsulinoma& sulfonyluria induced hypo. - Plama sulfonyluria is present only when drug administered - plasma insulin values& C-peptide valuesexogenous insulin administration(Rxic overdose/deliberate suicidal or factitious) - Plasma concentration of ß-cell polypeptideshypoglycemia not mediated by insulin or insulin like factor Urgent Treatment 1-Oral treatment prefered -20-30gm of glucose(in form of fast acting CHO-hard candy,glucose tab.,sweetened fruit etc..) -this should be followed by long acting CHO to prevent recurrent sxs. 2-Parentral therapy -if neuroglycopenia precludes oral feeding the patient needs IV glucose 25gm using 50%solution followed by constant 5-10%dextrose infusion. If IV Rx is not practical especially in T1DM SC or IM glucagon o.5-1mg will result in recovery of consciousness in 10-15 min. Prevention of recurrent hypo D/C offending drug or dose Treat underlying critical illness Replace deficient hormones.eg-cortisol&GH Surgical,radiotherapeutic or chemo of non- ß-cell tumor. Resect 10 pancreatic tumors-insulinoma Auto immune hypoglycemia-often self limiting glucosidase inhibitor for post prandial hypo due to surgery(delays CHO digestion& glucose absn.) Frequent feeding & avoidance of fasting. Recommendations For all insulin Rxed patients particulrly those about to begin intensive insulin: -Take detailed Hx-major episodes,frequency,how treated -Intensive therapy-increase risk so explain to the patient -Check adequacy of counterregulatory hormone. -Education for patient-recognition & Rx hypo. -Education for family & friends –recognition & treatment of hypo. -At every clinic visit ask about hypoglycemia,check bld.glucose measuring equipment as well if possible REFERENCES WILLIAMS ENDOCRINOLOGY UPTODATE 14.1 HARRISON’S 16TH EDITION INTERNET SOURCES THANK YOU